Detoxication of active pharmaceutical substances using cyclodextrine oligomers

ABSTRACT

A cyclodextrin oligomer comprising two cyclodextrins connected through a spacer at the secondary side, characterized in that said spacer comprises the unit B which is a rigid and preferably hydrophilic structural element.

The present invention relates to spacer-bridged cyclodextrin oligomers,and to complexes of such cyclodextrin oligomers with pharmaceuticallyactive substances.

Cyclodextrins are circular glucose polymers which are referred to as α-,β- or γ-cyclodextrins, depending on the number of glucose units (6 to 8,respectively). A lipophilic cavity exists inside the oligoglucose ring.It is known that lipophilic substances can be enclosed within thiscavity. Cyclodextrins are used, inter alia, for converting compoundshaving low solubility to a soluble complex by complex formation withcyclodextrin.

In Tetrahedron, Vol. 51, 2 (1995), p. 377-388, R. Breslow et al.describe cyclodextrin dimers which are capable of binding substrateshaving the correct geometry in aqueous solutions.

In the Journal of Inclusion Phenomena and Molecular Recognition inChemistry, 27 (1997), p. 69-84, A. Ruebner et al. describe dimericcyclodextrins having high binding affinities for porphyrinoidphotosensitizers as a carrier system for the application of drugs inphotodynamical cancer therapy.

In Tetrahedron Letters 25 (1984), p. 5533-5536, K. Fujita et al.describe the preparation of ditosylates of β-cyclodextrin and theirpurification by reversed-phase chromatography.

In Tetrahedron Letters 18 (1977), p. 1527-1530, I. Tabushi et al.describe the specific bifunctionalization of cyclodextrin.

In Arch. Microbiol. 165 (1996), p. 206-212, R. Feederle et al. describethe purification and characterization of the enzyme cyclodextrinase fromKlebsiella oxytoca.

In an electronic publication which is accessible underhttp://antas.agraria. uniss.it/electronic_papers/eccc3/bcd/welcome.htm,B. Manunza et al. describe a molecular dynamics study of the structureand internal movement of solvated β-cyclodextrin.

In the Journal of Pharmaceutical Sciences 84 (1995), p. 1223-1230, U. S.Sharma et al. describe the pharmaceutical and physical properties ofpaclitaxel (taxol) complexes with cyclodextrins.

In SPIE Biomedical Optics 3191 (1997), p. 343-353, A. P. Savitsky et al.describe an avidin-biotin system for the selected transport ofphotosensitizers and other cytotoxic agents into tumor tissue.

In Eur. J. Nucl. Med. 20 (1993), p. 1138-1140, F. Fazio & G. Paganellidescribe that such biotin-avidin systems enable a highly specificlabeling of tumors.

It has been the object of the present invention to provide cyclodextrinoligomers which are suitable for the inclusion of pharmaceuticallyactive substances due to their geometry.

The cyclodextrin oligomers according to the invention are twocyclodextrins connected through a spacer at the secondary side, thespacer comprising the unit B which is a rigid and preferably hydrophilicstructural element. In one embodiment, the cyclodextrin oligomers havethe general formula

CD—X—A—X—B—X—A—X—CD

where

each X is independently selected from —NH—, —O—, —S—, —CO— or a covalentbond;

each A is an aliphatic C₂ to C₄ residue or a covalent bond;

B is a rigid and preferably hydrophilic structural element; and

each CD represents a cyclodextrin bound through its secondary side.

Preferred compounds for the unit B include melamine, trimesic acid,alizarintetracarboxylic acid or tetraaminoalizarin, and cyclodextrins,such as α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin, thecyclodextrins being preferably bound through their primary sides.

As examples of the cyclodextrin oligomers according to the invention,there may be mentioned the compounds:

di-β-CD(—NH—(C₈H₁₆)—NH—);

di-β-CD(terephthaldiamide);

di-β-CD(—NHCO(trimesyl)CONH—);

di-β-CD(—NH—(C₃H₆)—NHCO—(C₃H₆)—CONH—(C₃H₆)—NH—);

di-β-CD(—NH—(C₂H₄)—NHCO(trimesyl)CONH—(C₂H₄)—NH—);

di-β-CD(—NH—(C₂H₄)—SH—[6-α-CD-6]—SH—(C₂H₄)—NH—);

di-β-CD(—NH—(C₄H₈)—NHCO—(C₃H₆)—COHN—(C₄H₈)—NH—);

di-β-CD(—NH—(C₂H₄)—SH-[6-(β,γ)-CD-6]-SH—(C₂H₄)—NH—); or

di-β-CD(—NH—(C₃H₆)—NHCO(trimesyl)COHN—(C₃H₆)—NH—).

The cyclodextrin oligomers according to the invention can be obtained bythe tosylation of the OH groups on the secondary side of cyclodextrins,followed by reaction with short bifunctional spacer groups. The thusobtained functionalized cyclodextrins can be converted to dimers withbifunctional reagents. The corresponding synthetic protocols can befound in A. Ruebner et al. (loc. cit.). Alternatively, carboxylic acidfunctions may also be introduced into the cyclodextrins by reacting theregiospecific tosylates with amino- or mercaptocarboxylic acids, such as3-mercaptopropionic acid or 4-aminobutyric acid.

Binding constants can be determined in competition with6-(p-toluidino)-2-naphthalenesulfonic acid (TNS). The measurement isperformed by fluorescence spectroscopy according to Ruebner et al. (loc.cit.).

Preferably, the cyclodextrin oligomer additionally carries at least oneand preferably two affinity groups which can interact with moleculartarget structures.

In principle, said at least one affinity group can have bindingcapability for a tissue-specific antigen as a molecular targetstructure. However, according to the polyphasic application route soughtby Fazio & Paganelli (loc. cit.), an indirect tissue-specific binding ispreferred: The affinity group recognizes a target structure which waspreviously attached at the desired site of action in a tissue-specificway.

For example, a possible site of action is a tumor. Thus, a tissue- ortumor-specific antibody which carries the target structure for theaffinity group of the substance according to the invention can first beintroduced into the organism once or several times to become enriched atthe site of action, in terms of a polyphasic tumor therapy.Subsequently, a selective enrichment of the pharmaceutically activesubstance can be achieved at the site of action by the administration ofa complex of a pharmaceutically active substance and the substanceaccording to the invention having the affinity group. Then, thepharmaceutically active substance can be released at the site of action.This is effected, for example, by disrupting the cyclodextrin unit(s) atthe site of action. Poly- or monoclonal antibodies, but also antibodyfragments, such as Fab or F(ab)₂ fragments, and artificial antibodiessuch as scFv fragments, can be used as said antibodies. Suitableaffinity groups and target structures include a wide variety of bindingmembers, such as biotin/avidin, biotin/streptavidin or enzyme/inhibitorsystems. Preferred affinity groups include biotinyl residues anddigoxin/digoxigenin residues.

Therefore, the invention further relates to a complex of apharmaceutically active substance and the cyclodextrin oligomersaccording to the invention. These physical inclusion complexes, whichare highly hydrophilic externally, serve to prevent the uptake of thecomplexed pharmaceutically active substance into body cells for thepurpose of reducing or excluding the side-effects of tumor therapeutics,for example. Preferably, the pharmaceutically active substance has ahigh potential for side-effects and can therefore be employed in itsfree form only in a limited way. Suitable pharmaceutically activesubstances include mitotic inhibitors, tumor therapeutics andphoto-chemotherapeutics, especially taxol, a taxol derivative,coichicine, colchemide, 3¹,8¹-(di-t-butylphenoxy)porphyrin,chlorotrianisene, tamoxifene, vinblastin, vincristin, docetaxel.

If the cyclodextrin oligomers carry an additional affinity group, theycan serve for the selective polyphasic application of a pharmaceuticallyactive substance. Surprisingly, the side-effects of a therapy can bereduced by this method. In addition, a considerable dosage reduction ofup to a factor of 10,000 is possible.

The invention also relates to medicaments which contain at least onecyclodextrin oligomer according to the invention or at least one complexaccording to the invention. Such medicaments are useful, in particular,for the treatment of tumor diseases, such as tumors of the bladder,carcinomas of the breast or uterus, esophageal cancers, gastriccarcinomas, cephalo -cervical carcinomas, nasopharynx carcinoma,hepatocellular carcinomas, pulmonary carcinomas, lymphomas, melanomas,ovarial carcinomas and prostatic carcinomas.

In a preferred embodiment, the cyclodextrin oligomer isdi-β-CD(—NH—(C₄H₈)—NHCO—(C₃H₆)—CONH—(C₄H₈)—NH—), and thepharmaceutically active substance is taxol or a taxol derivative.

The indication, dosage and successes of treatment in tumor diseases aredescribed in: Proceedings ASCO, Vol. 16 (1997) (Denver, Colo., USA).

Due to the cyclodextrins being bonded on the secondary side, thecavities of the cyclodextrins are oriented towards each other. Thecyclodextrins are preferably β-cyclodextrins. The distance between thecyclodextrin units is determined by selecting the spacer. Depending onthe size of the compound to be enclosed, the spacer is selected suchthat the distance between the at least two cavities approximatelymatches the distance between two hydro-phobic groups of thepharmaceutically active substance. Preferred spacings are within a rangeof about 0.6 to 2 nm, more preferably in a range of about 0.8, 1.0, 1.2,1.4, 1.6 and 1.8 nm. Such compounds are shown in the following Table.

Inclusion of various homo- and heteroditopical pharmaceuticals into“tailor-made” dimeric or trimeric β-cyclodextrin oligomers: Structureand spacing length of the spacers Length of the spacer Spacer structurefor Spacer structure Affinity constant, possible Δ [Å] dimers fortrimers measured/estimated [l/mol] guest compounds For spacer Δ ≦ 6 Å,see ref. Breslow et al. (1995) 7-8 octyl-α,ω-diamide = ./. 10⁶-10⁷3¹,8¹-(di-t-butylphenoxy)- (—NH—(C₈H₁₆)—NH—) porphyrinoids for PDT****,(tamoxifene), phenytoin as standard substance  9-10 —NHCO(trimesyl-X**-./. 10⁶-10⁷ chlorotrianisene, biotinyl)CONH— tamoxifene 11-12 A3C5A3***= —NH— ./. 10⁶-10⁷ colchicine*, colchemide* (C₃H₆)—NHCO—(C₃H₆)—CONH—(C₃H₆)—NH— 13-14 —NH—(C₂H₄)—NHCO(tri- —NH—(C₂H₄)—SH— ˜10⁸vinblastin*, vincristin* mesyl-X**-biotinyl)- [6-α-CD-6]—SH—CONH—(C₂H₄)—NH— (C₂H₄)—NH— 15-16 A4C5A4*** = —NH— —NH—(C₂H₄)—SH— 10⁷(dimer)- paclitaxel, docetaxel (C₄H₈)—NHCO—(C₃H₆)— [6-(β,γ)-CD-6]—SH— 3· 10⁹ (trimer) CONH—(C₄H₈)—NH— or- (C₂H₄)—NH— as in NH—(C₃H₆)—NHCO(tri-FIG. 1 mesyl-X**-biotinyl)- CONH—(C₃H₆)—NH— or alizarin derivative asshown in FIG. 2 Remarks: *hetero-ditopical; **trimesyl-X- =tricarboxybenzoylmonocadaveryl-; ***nomenclature according to Ruebner etal. (1998); ****PDT = photodynamical tumor therapy

The spacer between the two cyclodextrin units is rigid, i.e., the spacerhas only a small number of bonds which can freely rotate about thebinding axis. Preferably, the spacer contains an additional cyclodextrinunit which is preferably bound to the complexing cyclodextrins throughits primary side and through short aliphatic spacers.

Such rigid spacers can also be achieved by the use of appropriatelyfunctionalized (hetero)aromatics. For example, rigid spacers prevent toohigh a conformational flexibility, such as twisting of the twocyclodextrins involved in the binding. This results in comparably highbinding constants as stated in the above Table. By the use of rigidspacers, affinity constants within a range of greater than 10⁶,preferably greater than 10⁷ and more preferably greater than 10⁸ l/molare achieved. Thus, rigid spacers are those which achievecorrespondingly high stability constants of the complexes together withcyclodextrins involved in the binding and appropriate guest compounds.

The complexes according to the invention can be disrupted, for example,by the action of cyclodextrinase from Klebsiella oxytoca to release thecomplexed pharmaceutically active substance. Alternatively, functionalgroups can be contained in the spacers which facilitate the breaking ofthe bond at the target site.

FIG. 1 shows a scheme for the synthesis of a trimeric cyclodextrin.

FIG. 2 shows the structure of alizarin-bridged cyclodextrins derivatizedwith two biotinyl affinity groups.

FIG. 3 shows the fluorescence spectrum of the batch according to Example6. The encapsulated paclitaxel is monomerized.

FIG. 4 shows the influence of free taxol and complexed taxol accordingto Example 8 on the mitosis of OAT cells. The upper three lines(crosses, triangles, diamonds) represent the effect of non-encapsulatedtaxol, the curves of squares, triangles and circles represent the effectof encapsulated taxol, and the three curves (crosses) representuntreated cells.

FIG. 5 shows the reactivation of taxol from the complex by treatmentwith cyclodextrinase according to Example 8.

FIG. 6 shows the most probable structure of the paclitaxel/cyclodextrindimer complex.

The following Examples are intended to further illustrate the methodaccording to the invention.

EXAMPLE 1 Synthesis of a β-[1,6(A-D)]-capped Cyclodextrin and ItsFurther Conversion to β(6)-diamidopropyldiaminocyclodextrin

3 g of β-cyclodextrin (Wacker Chemie, Burghausen) which had been driedin an oven at 105° C. was dissolved in 50 ml of pyridine. A solution of1 g of 4,4-methylenebis(benzenesulfonic acid)dichloride in 50 ml ofpyridine was slowly added dropwise. The mixture was stirred at roomtemperature for 3 hours. Then, 10 ml of water was added, and allsolvents were removed in a rotary evaporator at 70° C. The remainingsirup was treated twice with water and evaporated, followed bydissolving in 10 ml of water and precipitation in 500 ml of acetone.MALDI mass spectroscopy showed a molecular weight of (M+Na⁺)=1451(1).

Substance (1) can be further purified by reversed-phase chromatography.

The substance was further treated with a tenfold excess ofdiaminopropane to obtain β-[6(A-D)]diamidopropanediaminocyclodextrin(2). Thus, a solution of substance (1) in hot water was added dropwiseto an aqueous solution of diaminopropane and stirred at 70° C. for 3hours. The product concentrated by evaporation was precipitated inacetone-methanol 20:1 and further purified by Soxhlet extraction withacetone-methanol (4:1).

Further purification is achieved by ion-exchange chromatography on SPSephadex with a gradient of water to 2 M triethylamine in water.

Similarly, α- and γ-cyclodextrin can be reacted with the reagent andfurther processed in the way described.

EXAMPLE 2 β-(2S)-monotosylcyclodextrin and Its Conversion top-(2)-cyclodextrin(3-thiopropionic Acid) orβ-(2S)-cyclodextrin(3-thiopyruvic Acid) or β-(2S)-cyclodextrin(2-thioacetic Acid)

2.5 g of 2-monotosyl-β-cyclodextrin prepared and purified according toRuebner et al. (1997) was dissolved in 40 ml of dimethylformamide (DMF).Further, 1.7 g of 3-mercaptopropionic acid was dissolved in 60 ml ofDMF, and 0.3 g of dry K₂CO₃ was added. This solution was heated at 70°C., and the first solution was added dropwise thereto. After three hoursof stirring, the solution was cooled, filtered and evaporated in arotary evaporator. The sirupy residue was precipitated in acetone, andthe precipitate was dried. Further chromatographic purification waseffected on QAE Sephadex with elution by a gradient of 0 to 2 M formicacid. MALDI: (M+K⁺)=1263.

β-(2S)-cyclodextrin(3-thiopyruvic acid) (under an argon atmosphere) andβ-(2S)-cyclodextrin(2-thioacetic acid) can be prepared in a similar way.

EXAMPLE 3 Formation of Trimers from the Substances of Examples 1 and 2

Several methods for the preparation of cyclodextrin trimers weresuccessfully tried with the substances of Examples 1 and 2.

(A) The product from Example 2 was dissolved in a small volume of DMF, a20 fold molar excess of carbonyidiimidazole was added, and the solutionwas heated at 70° C. for 30 min. A small amount of N-hydroxysuccinicamide was added. Then, a two-and-a-half-fold molar excess of thesubstance from Example 1 was added, and the solution was stirred for 2hours. The product was concentrated in vacuo and precipitated withacetone. Further purification by sequential ion-exchange chromatographyon SP and QAE Sephadex yielded the pure trimer.

(B) The product from Example 2 was dissolved in a small volume ofaqueous phosphate buffer (pH 5.5), and a 20 fold molar excess of EDACand a small amount of N-hydroxysuccinic imide were added. After 30 min,a 2.5 fold molar excess of the substance from Example 1 in an aqueoussolution was added dropwise. The reaction mixture was allowed to standin a cool room at 4° C. for 4 days with stirring. Further purificationwas performed as described under (A).

(C) Purified capped cyclodextrins could be directly reacted withcysteamine in DMF to give dicysteaminylcyclodextrins. The products wereprecipitated in acetone and further reacted with 2-tosyl-β-cyclodextrinat 70° C. in DMF. These short-chained trimers could be further purifiedby reversed-phase chromatography on Lichroprep RP8.

EXAMPLE 4 Formation of Physical Inclusion Complexes Between aPharmaceutically Active Substance and Trimeric Cyclodextrins Accordingto Example 3. General Method and Purification of the Complexes

The pharmaceutically active substances were dissolved in ethanol ordimethyl sulfoxide for complexation and added to a substance accordingto Example 3 in water or phosphate-buffered physiological saline (PBS).The solutions were heated at 70° C. in a rotary evaporator and brieflyevacuated to remove the ethanol. After cooling, the solutions werecharged on a column with TSK gel and eluted with water or PBS. The firstfractions (which may be colored) contain the pure complex.

EXAMPLE 5 Biological Testing with Complexes According to Example 4.Injections and Infusions in Test Animals

Purified complexes according to Example 4 were injected intravenouslyinto mice or rats in doses of from 2 to 5 mg/kg in accordance with thequantitative assay by fluorescence or absorption spectrometry. The urineand faeces of the animals were collected. After 24 hours, the animalswere sacrificed, and their organs processed for fluorescence analysis.This is preferably effected by extraction with methanol:acetone 1:1since the complexes according to the invention can be dissociated usingthese solvents. Less effective is the dissolution of organ homogenizatesin 2% sodium dodecylsulfate in aqueous solution, followed byfluorescence spectroscopy. In this way, the quantity of the bound guestmolecule in different organs can be determined, and thus, conclusions asto the pharmacokinetics of the complexes can be drawn.

EXAMPLE 6 Encapsulation of Taxol into the CD Dimer

250 mg (100 μmol) of the CD dimer di-β-CD(2N-A4C5A4) (see FIG. 5) wasdissolved in 1 l of aqueous buffer (pH 7.35, Hepes 25 mM) at 60° C. andkept at this temperature with vigorous stirring. 8.5 mg of paclitaxel(10 μmol) was dissolved in 1 ml of dimethyl sulfoxide and added dropwiseto the mixture with vigorous stirring. The mixture was kept at 60° C.for 24 hours with stirring, followed by cooling and freeze-drying themixture. The fluorescence spectrum (FIG. 1) shows the monomerization ofthe complexed taxol.

In a competitive reaction with toluidinonaphthalenesulfonic acid, acomplex binding constant K_(taxol=)1.4 μM is found. Complex formationcan be performed similarly with CD dimers to which biotin is attachedthrough a C5 spacer (cadaverine). The binding capability of biotin toavidin is not affected by such treatment at 60° C.

EXAMPLE 7 Purification of the Complex by Gel Chromatography on TSK Gel

The mixture was dissolved in 10 ml of water and charged onto achromatographic column (3×100 cm) filled with TSK gel. Upon fractionatedelution with water, the 1st peak contains the pure complex purified fromaccompanying materials. Detection was effected in a flow mode at 260 or280 nm. The product was sterilized from the eluate by filtration througha sterile filter with 0.2 μm pore size.

EXAMPLE 8 Testing of the Complex for Toxicity in a Cell Culture

1/1000 of the complex purified according to Example 2 (=10 nmolpaclitaxel) was dissolved in 250 ml of DMEM culture medium (finalconcentration 40 nM). A similar charge was prepared withnon-encapsulated taxol. The charges were added to culture cells (OATSCLC), and the number of rounded cells (=cells in inhibited mitosis) wascounted every 3 hours. The complexed taxol showed no mitosis-inhibitingeffect on the culture cells within 24 hours (FIG. 2).

Treatment of the complex with the enzyme cyclodextrinase (fromKlebsiella oxytoca) showed the release and reactivation of the complexedtaxol from the complex in a similar experimental set-up (FIG. 3).

EXAMPLE 9 Specific Targeting of the Taxol Complex for Tumors of Mice

Xenografted OAT SCLC cells on nude mice were allowed to grow for 1 weekfor tumor formation. Thereafter, the mice were pretreated with thebiotinylated monoclonal antibody ICO 25 for 24 hours by intraperitonealinjection of 1 mg of antibody per mouse. Then, 5 mg of NeutrAvidin wereinjected intraperitoneally. After an additional 48 hours, the complexformed from biotinylated (BiotinCadaverin)-CD dimer and paclitaxel(1-2-5 mg/mouse) was injected, and the growth of the tumor was followedover 4 weeks. The treated tumors grow at a maximum rate of 15% of thegrowth rate of untreated tumors (1-2 mg/mouse) or are completelyeliminated (5 mg/mouse). Side-effects occurring with non-encapsulatedtaxol are not observed.

What is claimed is:
 1. A cyclodextrin oligomer having the generalformula CD—X—A—X—B—X—A—X—CD wherein X—A—B—X—A—X is a bifunctional spacerin which: each X is selected from the group consisting of —NH—, —O—,—S—, —C(═O)— and a covalent bond; each A is selected from the groupconsisting of a C₂ to C₄ alkylidenyl residues and a covalent bond; B isselected from the group consisting of diradical linkers derived frommelamine, 1,3,5-benzenetricarboxylic acid (aka trimesic acid), atetracarboxylic acid derivative of 1,2-dihydroxyanthraquinone, atetraamino derivative of 1,2-anthraquinone, α-cyclodextrin,β-cyclodextrin and γ-cyclodextrin; wherein each said cyclodextrin isbound through two primary carbons; and each terminal CD is bound througha secondary carbon; and wherein said cyclodextrin oligomer is optionallysubstituted with at least one affinity group which interacts with amolecular target structure.
 2. The cyclodextrin oligomer according toclaim 1, selected from the group consisting of:1,3-{2^(o)[β-CD]—N(H)—C(═O)}-5-carboxybenzene;1,3-{2^(o)[β-CD]—N(H)—C₂H₄—N(H)—C(═O)}-5-carboxybenzene;β-CD—NH—(C₂H₄)—S-(α-cyclodextrin)-S—(C₂H₄)—NH-β-CD;β-CD—NH—(C₂H₄)—S-(β-cyclodextrin)-S—(C₂H₄)—NH-β-CD;β-CD—NH—(C₂H₄)—S-(γ-cyclodextrin)-S—(C₂H₄)—NH-β-CD; and1,3-{2^(o)[β-CD]—N(H)—C₃H₆—N(H)—C(═O)}-5-carboxybenzene.
 3. Thecyclodextrin oligomer according to claim 1, wherein said at least oneaffinity group is covalently bound to B of said spacer.
 4. Thecyclodextrin oligomer according to claim 1, wherein said at least oneaffinity group is a biotinyl residue or a digoxin/digoxigenin residue.5. A physical inclusion complex consisting of a cyclodextrin oligomeraccording to claim 1 and a pharmaceutically active substance havingrestricted usage because of its high potential for undesirableside-effects.
 6. The physical inclusion complex according to claim 5,wherein said pharmaceutically active substance is selected from thegroup consisting of mitotic inhibitors, tumor therapeutics andphotochemotherapeutics.
 7. The physical inclusion complex according toclaim 5, wherein said pharmaceutically active substance is selected fromthe group consisting of taxol, a taxol derivative, colchicine,colchemide, 3¹,8¹-(di-t-butylphenoxy)porphyrin, phenytoin,chlorotrianisene, tamoxifene, vinblastine, vincristin and docetaxel. 8.A method for the preparation of the physical inclusion complexes ofclaim 5 comprising the steps of: dissolving at least onepharmaceutically active substance in a first solvent to form a firstsolution; dissolving a cyclodextrin oligomer according to claim 1 in asecond solvent to form a second solution; combining said first andsecond solutions to form a combined solution; and heating said combinedsolution to evaporate said first solvent to enclose saidpharmaceutically active substance within a physical inclusion complex ofsaid cyclodextrin oligomer.
 9. A method for the preparation of thecyclodextrin oligomers according to claim 1, comprising the steps of:functionalizing cyclodextrins on their secondary sides by activation ofOH groups on said cyclodextrins; and reacting said OH groups with shortbifunctional spacer groups.
 10. A pharmaceutical composition comprisinga physical inclusion complex according to claim 5 together with apharmaceutically acceptable carrier.
 11. A method of minimizing the sideeffects in the treatment of tumor diseases selected from the groupconsisting of tumors of the bladder, carcinomas of the breast or uterus,esophageal cancers, gasteric carcinomas, cephalocervical carcinomas,nasopharynx carcinoma, hepatocellular carcinomas, pulmonary carcinomas,lymphomas, melanomas, ovarial carcinomas and prostatic carcinomascomprising the steps of; administering to a patient at least onepharmaceutically active substance selected from the group consisting ofknown anti-neoplastic agents active against the listed diseaseconditions in the form of a cyclodextrin oligomer complex wherein saidcyclodextrin oligomer is defined by claim
 1. 12. The cyclodextrinoligomer according to claim 1, where two of said affinity groups areattached to said cyclodextrin oligomer.